delta4-3keto 14alpha-15alpha-oxido pregnenes



United States Patent '0" wan -r "a".

iZJQDKJSfiG A4-3 KETO wise-birth?) PREGNENES 4 Claims. *(Ci. ham- 239.53)

This invention is concerned with certain novel steroid compounds, and with novel methods of preparing them. In particular-it is concerned with steroid compounds having the formula wherein R is selected from the .group consisting of pf-hydroxyl and item, R -is selected from thelgroup consisting of hydrogen, hydroxyl and esters and ether's thereof containing from one to ten earbon atoms in the added moiety, and R is selected iirom the group consisting of hydroxyl and halogens. Of'cou-rse when R is B-hydroxyl, there will also be a hydrogen atom on 11 position carbon atom. This application is in part a continuation of our copending application Serial NO. 432,621, filed May 26, 1954, now abandoned.

The starting materials for these syntheses are coinpounds having the formula These syntheses involve the steps outlined below. The.

Patented Sept. 15, 1959 ice The term strong acid is used todes'eribe a suhstah'ee which, when 'di'sselved in water, --iOiiiZ-S to at least as great extent "as does acetic acid, which yields hydrogen ions. A substance is non oxidizing when none of "the atoms of the substance undergoes --a deerease in valance -'du'ring the reaction. Other u eful non-oxidizin str'oiig acids include, for example, hynrechler ic ac'ia and oxalic acid. Various solvents' may be used in placeof benzene. Those that have some value 'for this urpose include toluene, chloroform, earbontet rachleride, eyclohexane and 'dioxane.

The A co'r'npounds obtained in this "way are then treated with an oxidizing agent. Various reageiits of this type t'nay be used. Particularly useful are reagents selected from "the group eonsistin of organic *peracids and eliminate "oxidizing agents, tor example, perbenzeic acid, perphthalic acid or sodium "eliminate, to give il'4a,l5z'-'epoxide compeunzis "of the following formula been opened up to give -a h'YdIOXYL-QTGUP a halogen, or two -hydroxyl groups, substituted in1pla'ce of the epoxstandard methods.

and

l----on All these products are included in the general formula as given at the beginning of the application.

To summarize, the steps in the syntheses comprise introduction of the double bond at the 14 position, forma 4 excretion and do not exhibit any androgenicity-side effects which are common to cortisone and hydrocortisone. Generally the adrenocortically active products are employed at the same dosage levels as is hydrocortisone, although somewhat larger dosages are possible and even desirable, obtained equivalent potency without unwanted side elfects. Topical administration is preferred in many instances, especially for therapy in inflammatory conditions. The usual pharmaceutically acceptable carriers are employed, for instance ointment bases, aqueous suspensions and the like.

The following examples are given solely for the purpose of illustration, and are not 'to be construed as limitations of this invention, many variations of which are possible without departing from its spirit or scope.

EXAMPLE I Formation of double bond at 14-p0siti0n A solution of p-toluenesulfonic acid in benzene was prepared by taking up 400 mg. of the acid monohydrate in 150 ml. of benzene and boiling off a few milliliters of benzene-water azeotrope. The acid solution was then added to 4 grams of 14a-hydroxyhydrocortisone-2l-acetate in 650 ml. of benzene and the mixture heated for 4 hours under reflux in an apparatus containing a moisture trap. A nitrogen atmosphere was maintained throughout the reaction. The resultant solution was shaken vigorous- 1 .1y with water, twice was sodium bicarbonate solution, and

tion-of the epoxide ring at the 14a, 150a positions, and

opening the epoxide ring to give the final products.

It is, of course, apparent that to obtain optimum yields, care must be taken during these reactions to minimize side reactions at other positions in the molecule, for ex- I ample at the 11 position when it contains an OH group,

or at the 21 position When it contains, for instance, an ester group. Considerations such as these influence the choice of the particular reagent, the temperature, pH, solvent, and time of reaction to be used, optimum selections varying somewhat with the particular reaction.

As the 21 position hydroxyl group is the only primary alcohol group present in any of the products, or reactants, it is readily selectively esterified or etherified by In general, esters and ethers containing from one to ten carbon atoms in the added moiety are thus formed without difficulty. These include such esters as the formate, acetate, propionate, trimethylacetate, benzoate, hemi-succinate, hemi-phthalate, and cyclohexanecarboxylate, and such ethers as the methyl, ethyl and benzyl. prepare the heavier esters and ethers directly from the 21-hydroxyl of the product, instead of esterifying or etherifying at the start and carrying the added group through the other step, although this is an alternative, and

In general, it is more convenient to is sometimes advantageous in the case of the lighter groups, acetate for example.

Each of these products is physiologically active. Many of them have especially marked adrenocortical type activity. Each has either a fi-hydroxyl or a keto group at the very important 11 position, and an a-hydroxyl group,

at the 14 position, which group is also of value.

Particularly noteworthy for their physiological activity are A -dehydrohydrocortisone, l4ix,l5a-oxido hydrocortisone and 14a-hydroxy-ISfi-flurohydrocortisone, as well as the related ll-ketones, their 2l-esters, and the 140chydroxy-15,Bbromo, chloro and iodo hydrocortisones. By the usual pharmacological tests (mouse thymus, rat thymus and anti-inflammatory) these compounds exhibit thymolytic and anti-inflammatory activity in the range of cortisone and hydrocortisone. Although they are somewhat less active than cortisone and hydrocortisone, it I should be stressed that this class of compounds is unique in that they do not cause sodium retention or potassium vfinally with water. crystalline residue triturated with a small amount of 21-position.

for 24 hours.

" covered.

The benzene was removed and the methanol. The product was purified by recrystallization, and found to be 11 8,17a,21-trihydroxy-4,l4-pregnadien- 3,20-dione-2l-acetate.

Treatment as described above was applied to 11,8,1411, 17u-trihydroXy-4-pregnene-3,ZO-dione. The reaction proceeded as before to yield 11 3,l7a-dihydroxy-4,l4-pregnadien-3,20-dione.

The same reaction was run using 14a,17a-dihydroxy-4- pregnene-3,1l,20-trione as the starting material. The product was 17a-hydroxy-4,l4-pregnadien-3,l1,20-trione.

In the same manner 17ot,21-dihydroxy-4,14-pregnadien- 3,11,20-trione was prepared from l4a-hydroxycortisone, which is also called 14a,17a,21-trihydroxy-4-pregnene- 3,ll,2 O-trione. Here again, standard methods were used to prepare the esters and ethers of the products.

To avoid needless repetition, it should be mentioned here that throughout this and all subsequent examples, in the cases of compounds which have an hydroxyl function on the 21-position, the compound having the free 21-OH group was used as the starting material, and so also were compounds-having various ester or ether groups at that The overall reaction is the same in all cases, and the 2l-position groups remained unchanged throughout. Used groups included formate, acetate, propionate, trimethylacetate, succinate, phthalate and cyclohexanecarboxylate among the esters, and methyl, ethyl and benzyl among the ethers, or, in general, hydrocarbon I EXAMPLE n Formation of epoxide Monoperphthalic acid (7.5 ml. of 0.25 molar ether solution) was added to a solution of 300 mg. of 11]3,17oc,21 trihydroxy-4,l4-pregnadien-3,ZO-dione-Zl-acetate in ml. of ethyl acetate. The mixture was stored in the dark The solution was washed with dilute aqueous sodium bicarbonate and with water, dried over magnesium sulfate and evaporated to dryness. A crude crystalline residue of 1lfi,1706,2l-iIlhYdIOXY-14oc,150cepoxido 4 pregnene 3,20-dionc-2l acetate remained. After recrystallization from methanol, platelets were re- This experiment was repeated, using perbenzoic acid instead of monoperphthalic acid, and repeated again, this time using aqueous potassium chromate instead of monoperphthalic acid. In each case a product identical with that described immediately above was obtained. Use of 5 EXAMPLE III Opening the epoxide ring to form halohydrins A solution of 500 mg. of 1113,l7a,21-trihydroxy-14a, 15a-epoxido-4-pregnene-3,20-dione-2l-acetate in 25 ml. of chloroform was treated at '-10 C. with 50 ml. of a saturated solution of anhydrous hydrogen bromide in chloroform. After one hour the chloroform solution was washed with water until neutral, then dried over sodium sulfate and evaporated to dryness. The solid residue was triturated with ether and recrystallized from an ethyl acetate-cyclohexane mixture. The product was 1118,1411, 17a,21-tetrahydroxy-15 3-bromo-4-pregnene 3,20 dione- 21-acetate.

When this experiment was repeated using hydrogen chloride instead of hydrogen bromide the product was the corresponding 11 8,14,17a,2l-tetrahydroxy-lSp-ehloro-4-pregnene-3,20-dione-2l-acetate. The corresponding 15fl-fluoro and iodo compounds were also prepared by using hydrogen fluoride and hydrogen iodide respectively in lieu of hydrogen bromide.

Each of these reagents was also employed using this technique to treat all the other 14a,15u-epoxides obtained as described in Example II. In each case the product was the corresponding l4a-hydroxy-l5fl-halo compound.

EXAMPLE IV Opening the epoxide ring to farm 14u,15B-glycols 11fl,17a,21 trihydroxy 14a,l5a-epoxido-4-pregnene- 3,20-dione was allowed to stand overnight at room temperature in contact with a water-dioxane solution containing a catalytic amount of perchloric acid. 1113,1404, 1513,17oz,21 pentahydroxy-4-pregnene 3,20-dione was recovered. There were also isolated several other bydroxylated hydrocortisones, among which were compounds whose properties were consistent with their formulation as isomeric glycols, i.e. compounds differing from the above in the configuration at the 14 and/or 15 positions. The mixtures were partially separated by fractional crystallizations, and the individual components were isolated by partition chromatography. The same result was obtained when trichloroacetic acid was used instead of perchloric acid.

In this fashion the epoxide rings of the other compounds made as described in Example II were opened. In all cases the corresponding l4u,15B-g1ycol was obtained along with other hydroxylated derivatives of the starting material.

PHYSICAL CONSTANTS OF REPRESENTATIVE COMPOUNDS 6 Analysis.Calcd. C23H3007Z C, H, 7.23. Found: C, 65.68; H, 7.14.

(3) 11p,l7u,21 trihydroxy l4a,l5u-epoxido 4-pregnene-3,20-dione. M.P. 225 -226.5

]dDiOXAno+ 6%? 16,800 A55; 3.0, 5.85, 6.07, 6.20 Analysis.-Calcd. for C H 0 C, 67.00; H, 7.50. Found: C, 66.65; H, 7.45.

(4) 17,21 dihydroxy 4,14 pregnadien-3,11,20-trione- Zl-acetate. M.P. 200-201.

Analysis.--Calcd. for C H O C, 68.98; H, 7.05. Found: C, 68.92; H, 6.86.

(5) 1711,21 dihydroxy 140:,150: epoxido-4-pregnene- 3,11,20-trione-21-acetate. M.P. 184-186.

[a]""+ 186.2 e3? 16,600 (6) 115,170: dihydroxy 4,14-pregnadien 3,20-dione.

[a],"+90.5 e32 14,600 These are approximate values; the sample was not an analytical one. (7) 11p,l4u,17u,21 tetrahydroxy 1518 chloro-4-pregnene-3,20-dione-21-acetate. M.P. 172-174 with decomposition.

This is an approximate value; the sample was not an analytical one.

What is claimed is:

1. A compound having the formula wherein R is selected from the group consisting of hydroxyl and keto, and R is selected from the group consisting of H, OH and esters thereof containing from one to ten carbon atoms in the added moiety.

2. 11fi,17a,21 trihydroxy 14a,15ot epoxido-M-preg References Cited in the file of this patent UNITED STATES PATENTS 2,599,481 Plattner June a, 1952 2,656,349 Ruzicka Oct. 20, 1953 2,830,935 Shull 'Apr. 15, 1958 FOREIGN PATENTS 653,480 Great Britain May 16, 1951 OTHER REFERENCES Plattner et aL: Helv. Chim. Acta, 1946, 29, pages 2023- ;15 2021. 

1. A COMPOUND HAVING THE FORMULA 